Research

Population-based evaluation of the effectiveness

of nirmatrelvir–ritonavir for reducing hospital
admissions and mortality from COVID-19
Kevin L. Schwartz MD MSc, Jun Wang MSc, Mina Tadrous PharmD PhD, Bradley J. Langford PharmD,
Nick Daneman MD MSc, Valerie Leung BScPhm MBA, Tara Gomes PhD, Lindsay Friedman MPH, Peter Daley MD,
Kevin A. Brown PhD

n Cite as: CMAJ 2023 February 13;195:E220-6. doi: 10.1503/cmaj.221608

Abstract
Background: A randomized controlled
trial involving a high-risk, unvaccinated
population that was conducted before
the Omicron variant emerged found
that nirmatrelvir–ritonavir was effective
in preventing progression to severe
COVID-19. Our objective was to evalu-
ate the effectiveness of nirmatrelvir–
ritonavir in preventing severe COVID-19
while Omicron and its subvariants
predominate.
Methods: We conducted a population-
based cohort study in Ontario that
included all residents who were older
than 17 years of age and had a positive
polymerase chain reaction test for
SARS-CoV-2 between Apr. 4 and Aug. 31,
2022. We compared patients treated
with nirmatrelvir–ritonavir with patients
who were not treated and measured the
primary outcome of hospital admission
from COVID-19 or all-cause death at
1–30 days, and a secondary outcome of
all-cause death. We used weighted
logistic regression to calculate weighted
odds ratios (ORs) with confidence inter-
vals (CIs) using inverse probability of
treatment weighting (IPTW) to control
for confounding.
Results: The final cohort included
177 545 patients, 8876 (5.0%) who were
treated with nirmatrelvir–ritonavir and
168 669 (95.0%) who were not treated.
The groups were well balanced with
respect to demographic and clinical char-
acteristics after applying stabilized IPTW.
We found that the occurrence of hospital
admission or death was lower in the
group given nirmatrelvir–ritonavir than in
those who were not (2.1% v. 3.7%;
weighted OR 0.56, 95% CI 0.47–0.67). For
death alone, the weighted OR was 0.49
(95% CI 0.39–0.62). Our findings were simi-
lar across strata of age, drug–drug interac-
tions, vaccination status and comorbid­
ities. The number needed to treat to
prevent 1 case of severe COVID-19 was 62
(95% CI 43–80), which varied across strata.
Interpretation: Nirmatrelvir–ritonavir
was associated with significantly
reduced odds of hospital admission and
death from COVID-19, which supports
use to treat patients with mild COVID-19
who are at risk for severe disease.

Antiviral therapies to treat COVID-19 and prevent severe out-
comes such as hospital admission and death are valuable tools
in the global pandemic response. The Evaluation of protease
inhibition for COVID-19 in high-risk patients (EPIC-HR) random-
ized controlled trial (RCT) of nirmatrelvir–ritonavir identified an
89% reduction in progression to severe COVID-19 in participants
at high risk of severe disease who were treated, compared with
placebo.1 However, the trial was conducted between July and
December 2021, which was before the emergence of the Omicron
variant that is less virulent than the progenitor virus, 2 and
excluded vaccinated people, as well as those taking medications
with potential drug interactions.1 The Evaluation of protease
inhibition for COVID-19 in standard-risk patients (EPIC-SR) trial
recently reported nonsignificant findings in a press release.3
In real-world evaluations of nirmatrelvir–ritonavir while the
Omicron variant and its subvariants were predominating, a sig-
nificant protective effect was seen in adults 65 years of age and
older in Israel.4 A retrospective cohort study involving patients with
COVID-19 who attended designated outpatient clinics in Hong Kong
between Feb. 16 and Mar. 31, 2022, identified a reduced risk of hos-
pital admission in adults when given nirmatrelvir–ritonavir, albeit
attenuated compared with the EPIC-HR trial.5 Studies that have
stratified participants by vaccination status identified similar
reductions in relative risk in vaccinated cohorts but with smaller
reductions in absolute risk because of the lower baseline risk of
hospital admission or death from COVID-19. 4,6,7 Observational
studies have risks of bias that include residual confounding and
immortal time bias.8

E220 CMAJ | February 13, 2023 | Volume 195 | Issue 6 © 2023 CMA Impact Inc. or its licensors
 In Ontario, nirmatrelvir–ritonavir became widely available
and funded for all patients in the community by April 2022,
with clinical criteria set by the government limiting access only
to patients who were older, had comorbidities or were under-
vaccinated.9,10 The Ontario COVID-19 Science Advisory Table pro-
vided clinical practice guidance to Ontario clinicians on the use
of therapeutics for COVID-19 with stricter high-risk criteria based
on patients who were most likely to benefit from the limited sup-
plies of antiviral drug at the time.11 A large proportion of patients
who received nirmatrelvir–ritonavir in Ontario would have been
excluded from the EPIC-HR trial population (e.g., those previ-
ously vaccinated or receiving concomitant medications with sig-
nificant drug–drug interactions). Observational data evaluating
use of nirmatrelvir–ritonavir can inform future policy and guidelines.
Our objective was to evaluate the effectiveness of nirmatrelvir–
ritonavir on health outcomes, including hospital admission
and death from COVID-19, while Omicron and its subvariants
predominated.
Methods
Study population and setting
We conducted a population-based cohort study in Ontario
(Canada’s most populous province) with a population of about
15 million in 2022. Ontario has publicly funded health insurance that
covers most of the population. The cost of nirmatrelvir–ritonavir
was covered for all Ontarians regardless of their health insurance
coverage. We assessed all people in Ontario between the ages of 18
and 110 years who had a positive polymerase chain reaction (PCR)
test for SARS-CoV-2 between Apr. 4, 2022, and Aug. 31, 2022, for
study inclusion. We excluded those who were not Ontario resi-
dents, or had invalid identifiers such as date of birth or death
before the test date. We also excluded patients who were admitted
to hospital or those with nosocomial infections before or on the
day of testing. The data were housed and analyzed at ICES using
unique encoded identifiers. ICES is an independent, nonprofit
research institute whose legal status under Ontario’s health infor-
mation privacy law allows it to collect and analyze health care and
demographic data, without consent, for health system evaluation
and improvement.
Study design
We used inverse probability of treatment weighting (IPTW) from
propensity scores to adjust for confounding in our observational
study. We defined a propensity score as the probability of treat-
ment assignment conditional on measured baseline covariates.12,13
Using the propensity score, IPTW weighted people who were
treated by the inverse probability of not receiving nirmatrelvir–
ritonavir and weighted those who were not treated with the
inverse probability of receiving nirmatrelvir–ritonavir. This
approach yielded a synthetic sample in which receipt of nirmatrelvir–
ritonavir was independent of measured baseline covariates. Using
IPTW obtains unbiased estimates of average treatment effects
(assuming no residual confounding).12 Owing to the low propen-
sity for receiving nirmatrelvir–ritonavir for some covariates, we
used stabilized weights, which reduced the variability of the
CMAJ | February 13, 2023 | Volume 195 | Issue 6
estimated treatment effect.14 We selected the variables included
in the IPTW a priori based on their clinically important risk of
confounding. The most important predictors of severe COVID-19
Research
in the literature include age, vaccination status and time from
last vaccine dose, previous COVID-19, comorbidities and cumu-
lative number of comorbidities.15,16 Therefore, we included age,
sex, number of doses of SARS-CoV-2 vaccine (0, 1, 2, or 3 or
more), previous SARS-CoV-2 infection, time from last vaccine
dose (14–89, 90–179, 180–269, or 270 or more d), individual
comorbidities (including chronic respiratory disease, chronic
heart disease, hypertension, diabetes, immune compromised,
autoimmune disease, dementia, chronic kidney disease and
advanced liver disease) (Appendix 1, Table S1, available at www.
cmaj.ca/lookup/doi/10.1503/cmaj.221608/tab-related-content),
long-term care residence, and high versus standard risk using
the definition from the Ontario COVID-19 Science Advisory
Table, which is based on age, number of comorbidities and
number of vaccine doses received.11
Data sources
We obtained prescription data for nirmatrelvir–ritonavir from
the Ontario Drug Benefit (ODB) database, which is more than
99% accurate in identifying the outpatient prescription medica-
tions dispensed.17 Nirmatrelvir–ritonavir was approved for use
by Health Canada on Jan. 17, 2022. Shortly thereafter, limited
supplies were available from select COVID-19 assessment cen-
tres in Ontario for use; however, these prescriptions were not
captured in the ODB. Beginning Apr. 4, 2022, publicly funded
access to nirmatrelvir–ritonavir from community pharmacies
became available for any Ontario resident who met the prov-
ince’s eligibility criteria (Appendix 1, Table S2). Dispensing
through community pharmacies increased rapidly and reached
about 85% of all nirmatrelvir–ritonavir prescriptions during the
study period. Therefore, to reduce the risk of misclassification
bias, we excluded anyone with a positive test result for SARS-
CoV-2 from 1 of 27 COVID-19 assessment centres that dispensed
nirmatrelvir–ritonavir because their exposure status could not
be determined using our data. We obtained SARS-CoV-2 test
results from the COVID-19 Integrated Testing (C19INTGR) data-
base, which contains all SARS-CoV-2 PCR tests (but not antigen
test results). Eligibility for PCR testing changed in December
2021 and was limited to specific groups, including those eligible
for therapeutics for COVID-19.
We obtained vaccination status from the COVAXON database,
a central data repository for SARS-CoV-2 vaccinations in Ontario
that is administered by the Ontario Ministry of Health.18 We
obtained comorbidity data from the Canadian Institute for
Health Information (CIHI) and Ontario Health Insurance Plan
(OHIP) databases, as well as other validated disease-specific
cohorts at ICES (Appendix 1, Table S1). We defined the index date
for people exposed to nirmatrelvir–ritonavir as the date the drug
was dispensed. A time-to-dispense (TTD) distribution was then
created for the treated cohort that we defined as the time in days
from testing positive to medication dispensing. To minimize
immortal time bias, we then assigned a random index date to the
untreated group based on the TTD distribution from those who
E221
 were treated. For example, 37% of the treated group was dis- with an overlap in days supplied and the dispense date of
pensed nirmatrelvir–ritonavir on day 0; therefore, if the random ­nirmatrelvir–ritonavir, where level 1 included any co-medications
uniform number generated for an unexposed person was contraindicated with nirmatrelvir–ritonavir (i.e., nirmatrelvir–­
Research

between 0 and 0.37, we assigned a value of 0 for TTD and their
index date was defined as their test date (Appendix 1, Figure S1).
We excluded any patient who died or was admitted to hospital
on or before their index date (dispense date for patients who
were exposed and simulated index date for those not exposed).
We obtained data for drug–drug interactions from ODB.
Based on the availability of data on medication prescriptions, we
limited the analysis of drug–drug interactions to patients older
than 70 years of age. We defined potential drug–drug interaction
as any severity level 1 or 2 co-medications with an ODB claim
ritonavir should not be prescribed as stopping the co-medication
is insufficient to mitigate drug–drug interaction) and level 2
included co-medications with clinically significant drug–drug
interactions that require a mitigation strategy while on
­nirmatrelvir–ritonavir (i.e., holding co-medication, dose or inter-
val adjustment, use of an alternative agent, management of
adverse effects and additional monitoring) according to the
Ontario COVID-19 Science Advisory Table guideline (Appendix 1,
Table S3). 19 We did not evaluate drug–drug interactions in
patients who were younger than 70 years of age.

Patients with positive PCR tests for SARS-CoV-2

Apr. 4 to Aug. 31, 2022
n = 242 536

Excluded
• Duplicate tests n = 12 264

Unique patients
n = 230 272

Excluded
• Patients who were tested at centres that dispensed
nirmatrelvir–ritonavir n = 30 166

Patients with nirmatrelvir–ritonavir data available

n = 200 106

Excluded
• Dispense date of nirmatrelvir–ritonavir before test date n = 1261

Patients tested on or before date of drug dispensing

n = 198 845

Excluded n = 21 300
• Patient data missing sex n = 7
• Patient data missing age or patient > 110 yr of age n = 59
• Patient < 18 yr of age n = 18 505
• Not a resident of Ontario n = 797
• Date of hospital admission or death on or before index date n = 1932

Final cohort
n = 177 545

Patients who received Patients who did not

treatment with receive nirmatrelvir–
nirmatrelvir–ritonavir ritonavir (controls)
n = 8876 n = 168 669

Figure 1: Cohort creation flow chart. Note: PCR = polymerase chain reaction.

E222 CMAJ | February 13, 2023 | Volume 195 | Issue 6

Outcomes
Our primary outcome was the composite of hospital admission
because of COVID-19 or all-cause death that occurred 1–30 days after
the index date. We ascertained hospital admissions from the Case
and Contact Management database (Public Health Ontario). This
information is provided by local public health units for public health
purposes and defines hospital admissions related to COVID-19 for
people who received treatment for COVID-19 while in hospital or if
their length of stay was extended because of COVID-19. This data-
base has similar rates of ascertainment of hospital admissions and
death compared to other administrative data sources.20 We obtained
data on death from either the Case and Contact Management data-
base or the Registered Persons DataBase.
Statistical analysis
We compared the distributions of unweighted and weighted (using
stabilized weights) covariates using standardized differences, with
a value of less than 0.1 reflecting a clinically unimportant differ-
ence. We used IPTW-weighted logistic regression models for each
of the 2 outcomes, with treatment as the only covariate, to ascer-
tain the treatment effect. We have presented the estimated treat-
ment effects as weighted odds ratios (ORs) with confidence inter-
vals (CIs); we considered p values less than 0.05 to be statistically
significant. Using the estimated probabilities of the outcomes for
treated and untreated groups derived from the weighted logistic
regression models, we calculated the number needed to treat
(NNT) with CIs. Preplanned stratified analyses included age (≥ 70
or < 70 yr), vaccination status (0, 1–2, or ≥ 3 doses), potential drug–
drug interactions in those older than 70 years of age (level 1,
level 2 or no drug–drug interactions identified), comorbidities (≥ 3
or < 3), long-term care residents, high or standard risk as defined
by the Ontario COVID-19 Science Advisory Table and time (April to
June 2022 or July to August 2022). We added time since last vac-
cination (14–179 or > 179 d) post hoc to the stratified analyses. We
analyzed the data using SAS enterprise guide version 9.4.
Ethics approval
This study was approved by the Ethics Research Board at Public
Health Ontario (2022–015.01).
Results
We identified 242 536 people who had a positive test result for
SARS-CoV-2 by PCR between Apr. 4, 2022, and Aug. 31, 2022. After
we applied the study inclusion and exclusion criteria, there were
8876 people who received nirmatrelvir–ritonavir and 168 669 peo-
ple who did not receive this treatment (Figure 1). Before weighting,
the cohort who received nirmatrelvir–ritonavir was predominately
70 years of age or older (72.5%), had received 3 or more vaccine
doses (84.8%), had fewer than 3 comorbidities (57.1%), were stan-
dard risk by Ontario COVID-19 Science Advisory Table criteria
(58.1%) and did not reside in long-term care (68.5%). For those
70 years of age or older, 66.7% had 1 or more potential drug–drug
interactions (Appendix 1, Table S4). Before weighting, major
between-group differences existed among almost all variables
that we evaluated (Table 1). Recipients of nirmatrelvir–ritonavir
CMAJ | February 13, 2023 | Volume 195 | Issue 6
were older, more likely to have 3 or more vaccine doses, had more
comorbidities, were more likely to meet high-risk criteria and more
likely to reside in long-term care. After weighting, all standardized
Research
differences were 0.03 or less, indicating no clinically important dif-
ferences between any covariates (Appendix 1, Figure S2). After
weighting, all standardized differences were 0.03 or less, indicating
no clinically important differences between any covariates.
In the weighted primary analysis, we found that people who
received nirmatrelvir–ritonavir and those who did not had a 2.1%
and 3.7% risk of hospital admission or death, respectively. The
weighted OR of hospital admission or death within 30 days was 0.56
(95% CI 0.47–0.67, p < 0.001) (Figure 2) and the weighted OR of death
alone was 0.49 (95% CI 0.40–0.60, p < 0.001) (Appendix 1, Table S5).
Results overall were similar in the stratified analyses by age, vaccine
status, comorbidities, drug–drug interactions and risk status
(Appendix 1, Figure S3). We observed a possible decrease in effect­
iveness over time with a weighted OR of 0.43 (95% CI 0.33–0.57) for
hospital admission or death between April and June 2022 and a
weighted OR of 0.67 (95% CI 0.52–0.86) in July and August 2022,
with a similar trend for death alone (Appendix 1, Table S5).
We calculated that the NNT was 62 (95% CI 43–80) people
treated with nirmatrelvir–ritonavir to prevent 1 hospital admis-
sion or death from COVID-19. There was substantial variability in
absolute risk reductions by strata, with NNT ranging from 28 (95%
CI 7–49) for unvaccinated people to 181 (95% CI 50–312) for those
younger than 70 years of age (Figure 2; Appendix 1, Figure S3).
Interpretation
We found that the use of nirmatrelvir–ritonavir in Ontario between
April and August 2022 was associated with a significant reduction
in the odds of hospital admission from COVID-19 or all-cause death
with a NNT of 62. Our findings were consistent across most strata of
age, drug–drug interactions, vaccination status and comorbidities;
however, the absolute risk reductions were substantially lower
in younger patients and those at lower risk of severe COVID-19.
The largest benefits were observed in patients who were under-
vaccinated or unvaccinated and people 70 years of age or older.
As far as we are aware, the EPIC-HR study is the only published
RCT on nirmatrelvir–ritonavir that reported a relative risk reduction
of 89% and an absolute risk reduction of 6% (NNT = 17) for the pre-
vention of severe COVID-19 illness. However, EPIC-HR was con-
ducted before the Omicron variant emerged and it excluded patients
who were vaccinated and those with drug–drug interactions.1
Unpublished results from the subsequent EPIC-SR trial involving
patients at lower risk of COVID-19 showed a nonsignificant 57% rela-
tive reduction in hospital admissions and death in a vaccinated sub-
group of patients.3 Our cohort was older and almost all vaccinated,
with most having potential drug–drug interactions, which is a differ-
ent patient population than in the EPIC-HR clinical trial.
After adjustment for substantial confounding and addressing
potential immortal time bias through the study design, we observed
a significant clinical benefit to use of nirmatrelvir–ritonavir,
albeit less than with the EPIC-HR trial. This may be because of differ-
ences in the patient population, underlying immunity in the popula-
tion, differences among circulating variants or study design.
E223
 A 2022 cohort study in Israel identified an adjusted hazard ratio all-cause death. Risk factors for severe disease include older age
for severe COVID-19 in patients 65 years of age or older of 0.27 (the single most important risk factor), as well as obesity, the num-
(95% CI 0.15–0.49) in those who received nirmatrelvir–ritonavir but ber of comorbidities and time from previous vaccination. Vaccina-
Research

only 0.74 (95% CI 0.35–1.58) in those 40–64 years of age. Their find-
ings were similar when further stratified by previous immunity to
SARS-CoV-2. This study was also a real-world evaluation with simi-
lar patient characteristics to ours, although the Israeli cohort
excluded patients with drug–drug interactions.4
Our study, in conjunction with previous clinical trials and
observational research, supports the effectiveness of nirmatrelvir–
ritonavir at reducing hospital admission from COVID-19 and
tion and immunity from previous infection are significantly protec-
tive.15 We observed potentially important differences in the absolute
risk reductions that may have implications for cost-effectiveness
evaluations. Differences between strata had overlapping CIs; we did
not compare these statistically, and any observed differences
should be interpreted with caution. Further stratification by differ-
ent age groups and risk factors may be helpful in the future to evalu-
ate the benefit in those younger than 70 years of age.

Table 1: Baseline population characteristics of participants who received and did not receive
nirmatrelvir–ritonavir before weighting with standardized differences

Unweighted population

No. (%) of patients*

Received Did not receive

nirmatrelvir–ritonavir nirmatrelvir–ritonavir Standardized
Variable n = 8876 n = 168 669 difference

Age, yr
Mean ± SD 74.3 ± 16.3 52.4 ± 21.0 1.17
Median (IQR) 77 (67–86) 50 (35–67)
Sex, female 5261 (59.3) 106 899 (63.4) 0.08
No. of vaccine doses
0 467 (5.3) 10 434 (6.2) 0.04
1 87 (1.0) 1625 (1.0) < 0.01
2 798 (9.0) 28 704 (17.0) 0.24
≥3 7524 (84.8) 127 906 (75.8) 0.23
Previous SARS-CoV-2 infection 412 (4.6) 11 670 (6.9) 0.10
Time from last vaccine dose, d
14–89 1453 (16.4) 17 438 (10.3) 0.18
90–179 3759 (42.4) 72 705 (43.1) 0.02
180–269 2405 (27.1) 46 190 (27.4) 0.01
≥ 270 1259 (14.2) 32 336 (19.2) 0.13
Ontario COVID-19 Science Advisory Table risk group11
High risk 3720 (41.9) 25 499 (15.1) 0.62
Standard risk 5156 (58.1) 143 170 (84.9) 0.62
Comorbidity
Chronic respiratory disease 3128 (35.2) 40 813 (24.2) 0.24
Chronic heart disease 2249 (25.3) 18 910 (11.2) 0.37
Diabetes 2996 (33.8) 27 954 (16.8) 0.40
Immune compromised 1412 (15.9) 10 102 (6.0) 0.32
Hypertension 6071 (68.4) 54 549 (32.3) 0.77
Dementia 2659 (30.0) 15 714 (9.3) 0.54
Autoimmune disease 1150 (13.0) 8504 (5.0) 0.28
Chronic kidney disease 1108 (12.5) 9867 (5.9) 0.23
Advanced liver disease 209 (2.4) 2110 (1.3) 0.08
Long-term care resident 2795 (31.5) 12 806 (7.6) 0.63
Note: IQR = interquartile range, SD = standard deviation.
*Unless specified otherwise.

E224 CMAJ | February 13, 2023 | Volume 195 | Issue 6

 Nirmatrelvir− Favours
nirmatrelvir– Favours
ritonavir Unexposed
ritonavir nirmatrelvir–ritonavir
Subgroup weighted, % weighted, % OR (95% CI) NNT (95% CI)

Research
Primary analysis 2.1 3.7 0.56 (0.47–0.67) 62 (43–80)
Age ≥ 70 yr 2.8 5.0 0.55 (0.45–0.66) 45 (31–59)
Age < 70 yr 0.3 0.8 0.34 (0.15–0.79) 181 (50–312)
No vaccine 3.0 6.6 0.44 (0.23–0.84) 28 (7–49)
Vaccine doses: 1−2 1.1 4.4 0.25 (0.12–0.50) 30 (16–44)
Vaccine doses: 3 or more 2.2 3.5 0.62 (0.51–0.75) 77 (46–108)
Last vaccine dose: 14−179 d 1.8 3.2 0.55 (0.42–0.70) 69 (41–98)
Last vaccine dose: 180 or more d 2.6 4.5 0.57 (0.44–0.74) 53 (29–77)
Comorbidities: 3 or more 1.2 2.3 0.54 (0.39–0.73) 97 (49–145)
Comorbidities: < 3 3.3 5.7 0.57 (0.46–0.71) 42 (26–59)
Long-term care resident 4.7 5.6 0.84 (0.66–1.06) 113 (35–261)
Not in long-term care 0.9 2.9 0.31 (0.23–0.43) 51 (39–64)
OST risk group: high 3.5 6.2 0.55 (0.44–0.68) 37 (24–50)
OST risk group: standard 1.1 1.9 0.59 (0.42–0.81) 126 (50–202)
April to June 2022 1.6 3.7 0.43 (0.33–0.57) 48 (33–63)
July to August 2022 2.6 3.8 0.67 (0.52–0.86) 83 (32–134)
DDI level 2 2.9 4.8 0.60 (0.48–0.76) 54 (30–79)
No DDI 2.6 5.5 0.46 (0.33–0.63) 34 (21–48)

0 0.5 1 1.5 1 50 100 150 200

OR (95% CI) NNT (95% CI)

Figure 2: Forest plot of weighted odds ratios (ORs) with 95% confidence intervals (CIs) for hospital admission from COVID-19 or all-cause death and
number needed to treat (NNT), at 30 days for the primary analysis and stratified analyses for patients who received nirmatrelvir–ritonavir compared
with those who did not. Note: DDI = drug–drug interaction, OST = Ontario COVID-19 Science Advisory Table.

Two-thirds of our cohort who were 70 years of age or older had
potentially clinically significant drug–drug interactions (Appendix 1,
Table S3), which reflects the numerous medications that have
important drug–drug interactions with ritonavir. Based on the
data sources used in this study, we were unable to confirm
whether patients were actually taking interacting medications
concurrently or determine if any potential drug–drug interactions
were appropriately mitigated at the time of nirmatrelvir–ritonavir
prescribing, which may have affected our estimation of drug–drug
interactions. Our results suggest that patients with COVID-19 and
level 2 drug–drug interactions can be effectively treated with
­nirmatrelvir–ritonavir, and that prescribers and pharmacists are
key in the evaluation for and mitigation of drug–drug interactions.
Limitations
Our cohort was limited to those with a positive test result for
SARS-CoV-2 by PCR and did not include those with positive test
results by only rapid antigen tests, which may limit the generaliz-
ability of our findings.
Nirmatrelvir–ritonavir was publicly funded for all Ontario resi-
dents; however, ODB captures only about 85% of nirmatrelvir–
ritonavir prescriptions. We excluded patients who were tested at
any of the 27 COVID-19 assessment centres where nirmatrelvir–
ritonavir was dispensed without an ODB claim to limit the risk of
misclassification bias. Our database indicated that the medica-
tion was dispensed, but we could not assess adherence. During
the study period, there was no use of molnupirivir as it was not
approved by Health Canada at that time. There was some out-
patient use of intravenous (IV) remdesivir, which we were unable
to identify in our administrative data, but the number of patients
in the untreated group who received IV remdesivir was likely to
be low and would bias the study toward the null.
Observational cohort studies have a risk of immortal time bias,
which we attempted to mitigate through imputing theoretical dis-
pensing dates for the untreated group. By imputing index dates
that mirror the treated groups’ distribution, we removed people
who were not treated from the cohort who may have experienced
the outcome before having the opportunity to receive nirmatrelvir–
ritonavir. However, some residual bias is possible. As a result of
excluding outcomes that occurred on the day of or before the index
date, the number of hospital admissions from COVID-19 that con-
tributed to the outcome was relatively small. However, we identi-
fied consistent results for the primary composite outcome and for
all-cause death alone. There was significant confounding because
nirmatrelvir–ritonavir is recommended for and limited to patients
who were at higher risk of the outcome. Although the IPTW method
successfully balanced the groups by all evaluated covariates, resid-
ual confounding is possible. Finally, the absolute risk reductions
reported in this study should be interpreted cautiously as they may
not reflect the true disease incidence in the population.
Conclusion
In this population-level evaluation of nirmatrelvir–ritonavir we
observed a significant reduction in the odds of hospital admission
from COVID-19 and all-cause death, which supports the ongoing use
of this antiviral drug to treat patients with mild illness who are at risk
of severe COVID-19. Although the relative effectiveness was similar
across the strata and risk groups that we evaluated, we observed
substantial variation in the absolute risk reduction, which suggests
that use of nirmatrelvir–ritonavir in populations at lower risk of

CMAJ | February 13, 2023 | Volume 195 | Issue 6 E225


COVID-19 may have limited population health benefits with impor-
tant implications for its cost-effectiveness evaluations. Ongoing
evaluation to monitor effectiveness in the population with new cir-
Research
culating variants is critical to inform optimal use over time.
References
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ant severity in Ontario, Canada. JAMA 2022;327:1286-8.
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application submission to U.S. FDA [press release]. New York: Pfizer; 2022 June 14.
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Competing interests: Tara Gomes has received a stipend from Indigenous
Services Canada for their role on the Drugs and Therapeutics Advisory
Committee. No other competing interests were declared.
This article has been peer reviewed.
Affiliations: Public Health Ontario (Schwartz, Wang, Langford,
Daneman, Leung, Friedman, Brown); ICES Central (Schwartz, Wang,
Tadrous, Daneman, Gomes, Brown); Leslie Dan Faculty of Pharmacy
(Tadrous, Gomes) and Dalla Lana School of Public Health (Langford,
Brown, Schwartz), University of Toronto; Toronto East Health Network
(Leung); Li Ka Shing Knowledge Institute of St. Michael’s Hospital
(Gomes); Sunnybrook Health Sciences Centre (Daneman), Toronto,
Ont.; Memorial University (Daley), St. John’s, NL
Contributors: All of the authors conceived the study and provided input
on the design and analysis plan. Jun Wang performed the analysis.
Kevin Schwartz drafted the manuscript. All of the authors provided
input for the interpretation of the analysis, provided critical edits for the
manuscript, gave final approval of the version to be published and
agreed to be accountable for all aspects of the work.
Content licence: This is an Open Access article distributed in accordance
with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0)
licence, which permits use, distribution and reproduction in any medium,
provided that the original publication is properly cited, the use is noncom-
mercial (i.e., research or educational use), and no modifications or adapta-
tions are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Funding: This project was funded by Public Health Ontario. Peter Daley
has received grants from the Canadian Institutes of Health Research,
the Janeway Foundation, the Memorial University Seed, Bridge and
E226 CMAJ | February 13, 2023 | Volume 195 | Issue 6
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20. Chung H, Austin PC, Brown KA, et al. Effectiveness of COVID-19 vaccines over
time prior to omicron emergence in Ontario, Canada: test-negative design
study. Open Forum Infect Dis 2022;9:ofac449.
Multidisciplinary Fund and the Public Health Agency of Canada. Tara
Gomes has received grants and contracts from the Ontario Ministry of
Health and the Ontario College of Pharmacists.
Data sharing: The data set from this study is held securely in coded form
at ICES. Although legal data-sharing agreements between ICES and data
providers (e.g., health care organizations and government) prohibit ICES
from making the data set publicly available, access may be granted to
those who meet prespecified criteria for confidential access (available at
https://www.ices.on.ca/DAS; email: das@ices.on.ca). The full data set
creation plan and underlying analytic code are available from the
authors upon request, with the understanding that the computer pro-
grams may rely upon coding templates or macros that are unique to ICES
and are therefore either inaccessible or may require modification.
Acknowledgement: The authors thank IQVIA Solutions Canada for use
of their Drug Information File.
Disclaimer: This study was supported by ICES, which is funded by an
annual grant from the Ontario Ministry of Health (MOH) and the Ministry
of Long-Term Care (MLTC). The analyses, conclusions, opinions and
statements expressed herein are solely those of the authors and do not
reflect those of the funding or data sources; no endorsement is intended
or should be inferred. Parts of this material are based on data or infor-
mation compiled and provided by the Canadian Institute for Health
Information (CIHI). However, the analyses, conclusions, opinions and
statements expressed in the material are those of the author(s), and not
necessarily those of CIHI.
Accepted: Dec. 23, 2022
Correspondence to: Kevin Schwartz, Kevin.schwartz@oahpp.ca